Multipotent neural progenitor cells (NPCs) may someday be utilized to treat many neurological disorders. NPCs are self-renewing, differentiate into all major neuronal lineages, and may possess the ability to integrate into and replace degenerated regions of the brain. Development of effective NPC-based cell replacement will require a greater understanding of the determinants that influence NPC proliferation and differentiation. Preliminary studies in our laboratory have demonstrated that the transcriptional repressor Hes6 (Hairy/Enhancer of Slipt 6) enhances neuronal differentiation of murine embryonic NPCs. The specific aims of this proposal will investigate the post-translational regulation of Hes6 expression, and determine how components of the Notch signaling pathway (including Hes1 and Mash1) influence the ability of Hes6 to promote differentiation in NPCs.